The field of this invention is the modification of metabolism to mimic caloric restricted conditions without the usual reduction in calorie content, specifically, by lowering the overall level of cytosolic reduced pyridine nucleotide (NADH), especially relative to the NAD+ level, by administration of a nutritional supplement composition based on a high throughput assay of suppression of NADH autofluorescence in Saccharomyces cerevisiae. 
Calorie restriction is the only experimental manipulation known to extend the life span of living organisms (Lin et al., 2002, Nature 418:344-348; Weindruch and Walford, 1998, The Retardation of Aging and Disease by Dietary Restriction, Charles C. Thomas, Springfield, Ill.; Roth et al., 2001, J. Clin. Endocrinol. Metab. 86:3292-3295). A major cause of aging is thought to result from the cumulative effects of cell loss over time (Cohen et al., 2004, Science 305:390-392). The proposed mechanism underlying extension of life span involves a shift from a state of growth and proliferation to maintenance and repair (Walford, Harris and Weindruch, 1987, J. Nutrition 117: 1650-1654; Weindruch et al., 1988, J. Gerentol. 43: 840-842; Yu, Masoro and McMahan, 1985, J. Gerentol. 40: 657-670).
Initially, calorie restriction was believed to extend life span by decreasing metabolic rate, decreasing mitochondrial oxygen consumption, and, therefore, attenuating oxidative stress. However, the exact opposite appears to be true evidenced by increases in mitochondrial content and oxygen consumption in response to calorie restriction (Nisoli et al., 2005, Science 310:314-317). Observations that calorie restriction does not increase life span when the gene encoding cytochrome c is deleted (Lin et al., 2002, Nature 418:344-348) or in the presence of electron transport inhibitors (Bishop and Guarente, 2007, Nutr. Rev. Genet. 8:835-844; Pankowski et al., 2007, Nature 447:550-555) suggest that mitochondria are critical factors in the phenomenon of life span extension by calorie restriction.
There are several mechanisms by which mitochondria may be responsible for the life-enhancing effects of calorie restriction (Guarente, 2008, Cell 132:171-176). However, our work suggests that the simplest and most likely explanation is that enhanced mitochondrial activity results in the depletion of reduced pyridine nucleotides (NADH) of the cytosol and the increased production of NAD+ and that lowering of the level of NADH results in life extension. Among the several determinants of life span, the one common thread that has emerged is a variety of species from yeast to rodents is a correlation with lowered levels of NADH.
The basis for life extension by lowered NADH and increased NAD+ is due in part to inhibition by NADH of SIR2, a key regulator of life span in a number of organisms including yeast, worms, flies, rodents and non-human primates (Bordone and Guarente, 2005, Nat. Rev. Mol. Cell Biol. 6:298-305). That the silent information regulator (Sir) proteins regulate life span is well known (Haigis and Guarante, 2006, Genes Dev. 20:2913-2921). In yeast, an extra copy of the SIR2 gene extends replicative life span by 50 percent, while deleting SIR2 shortens life span (Kaberlein et al., 1999, Genes Dev. 20:2570-2580). SIR2 encodes an NADP-dependent deacetylase which emerges as a critical mediator of calorie restriction (Guarente and Picard, 2005, Cell 120:473-482).
The mammalian SIR2 ortholog SIRT1 encodes an NAD-requiring NAD-dependent histone deacetylase required for chromatin silencing and life-span extension. NADH is a competitive inhibitor of SIR2. Therefore, an overall reduction in NADH will activate SIR2 and result in life extension.
Calorie restriction mimics modify metabolism to reduce NADH levels and increase NAD+ comparable to that achieved under calorie restriction conditions, without the usual reduction in calorie content.
With extended use, calorie restriction mimics up- and down-regulate gene expression and cellular proteins to resemble those associated with calorie-restricted profiles as well as to decrease insulin resistance (lower fasting blood glucose levels) and increase glucose uptake, also similar to changes seen in calorie restriction. The same life extending pathways that have been shown to increase health and life span in animal trials are modified.
Longevity regulatory genes in addition to the NAD dependent histone deacetylase silent information regulator (SIR2) include, as well, the Forkhead transcription factor FOXO (Giannakou and Partridge, 2005, Trends Cell Biol. 14:408-412).
There is a long felt need in the art to provide compositions for human and animal use which extend longevity and which improve function of metabolism, so as to benefit health and wellbeing.